This invention relates to novel substituted 1-benzazapines and derivatives thereof useful as antibacterials, to pharmaceutical compositions comprising such compounds, to processes for making these compounds and to methods of using these compounds for treating bacterial infections.
Benzazepine compounds are useful in a number of pharmaceutical applications. In particular, U.S. Pat. No. 5,786,353 discloses that tricyclic benzazepine is useful as a vasopressin antagonist. U.S. Pat. No. 5,247,080 discloses that substituted benzazepines are useful as intermediates for producing pharmaceutically active compounds, such as intermediates for compounds that have valuable properties in treating psychosis, depression, pain and hypertension. WO 97/24336 discloses a process for the aminocarbonylation of benzazepines and benzodiazepines. These compounds are used as intermediates for preparing pharmaceutically active compounds.
There have been other processes for the preparation of benzazepines. Tetrahydro-1-benzazepines and tetrahydro-1,4-benzodiazepines form the core structure of a variety of pharmaceutically useful compounds. In particular, WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose 7-aminocarbonyl tetrahydro-1-benzazepines and tetrahydro-1,4-benzodiazepines which are reported to be inhibitors of the fibrinogen and vitronectin receptors and useful as inhibitors of platelet aggregation, osteoporosis, angiogenesis and cancer metastasis.
Methods to prepare such compounds typically employ a trisubstituted phenyl derivative as a starting material. The trisubstituted phenyl derivative incorporates two substituents to form the azepine and/or diazepine ring, and a third substituent to introduce the 7-carbonyl substituent. Such starting materials may be difficult and costly to obtain, and may limit the chemistry which may be employed to form the azepine ring. Prior processes generally introduce the aminocarbonyl group into the molecule via a 7-carboxyl group which is coupled to an amino group by conventional methods for forming amide bonds. Methods disclosed in WO 93/00095 and WO 94/14776 are exemplary.
Bacterial infections are a significant and growing medical problem. They occur when the body""s immune system cannot prevent the invasion and colonization of the body by disease-causing bacteria. These infections may either be confined to a single organ or tissue, or disseminated throughout the body, and can cause many serious diseases, including pneumonias, endocarditis, osteomyelitis, meningitis, deep-seated soft tissue infections, bacteremia and complicated urinary tract infections.
According to estimates from the United States Centers for Disease Control and Prevention (the xe2x80x9cCDCxe2x80x9d) in 1995, approximately 1.9 million hospital-acquired infections occurred in the United States, accounting for more than $4.5 billion in additional health care costs each year and contributing to more than 88,000 deaths. While overall per capita mortality rates declined in the United States from 1980 to 1992, the per capita mortality rate due to infectious diseases increased 58% over this period, making infectious diseases the third leading cause of death in the United States.
Antibiotics are administered both to prevent bacterial infections and to treat established bacterial diseases. When administered to prevent an infection, antibiotics are given prophylactically, before definitive clinical signs or symptoms of an infection are present. When administered to treat an established infection, antibiotics are often chosen empirically, before diagnostic testing has established the causative bacterium and its susceptibility to specific antibiotics.
Antibiotics work by interfering with a vital bacterial cell function at a specific cellular target, either killing the bacteria or arresting their multiplication, thereby allowing the patient""s immune system to clear the bacteria from the body. Currently available antibiotics work on relatively few targets, through mechanisms such as inhibiting protein or cell wall synthesis. These targets tend to be present in all bacteria and are highly similar in structure and function, such that certain antibiotics kill or inhibit growth of a broad range of bacterial species (i.e., broad-spectrum antibiotics).
Major structural classes of antibiotics include beta-lactams, quinolones, macrolides, tetracyclines, aminoglycosides, glycopeptides and trimethoprim combinations. Penicillin, a member of the beta-lactam class (which also includes extended-spectrum penicillins, cephalosporins and carbapenems), was first developed in the 1940s. Nalidixic acid, the earliest member of the quinolone class, was discovered in the 1960s. The creation of broad-spectrum antibiotics began in the 1970s and 1980s, with major advances seen in the 1970s with the development of newer beta-lactams, and in the 1980s with the development of fluoroquinolones. These antibiotics are still being used extensively. No major new class of antibiotics has been discovered and commercialized in the last 20 years. There remains a need to identify new classes of antibiotics to fight bacterial infections and to overcome the increasing resistance by bacteria to currently marketed antibiotics.
However, none of the prior teachings, described above or elsewhere, disclose the novel 1-benzazepine compounds of the present invention or that 1-benzazepines would be useful as antibacterial agents.
It is therefore an object of this invention to prepare 1-benzazepine derivatives that are useful as agents for the treatment of bacterial, viral or fungal infections both in vivo (including but not limited to parenterally and topically) and for inhibiting bacterial, viral or fungal growth, for example on surfaces and in solution.
The instant invention is directed to novel substituted 1-benzazepine compounds of the Formula (I): 
wherein:
R1 is H, with the proviso that R4 and R5 are not both H, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, xe2x80x94(CH2)mC(xe2x95x90O)R, xe2x80x94(CH2)nCN, xe2x80x94(CH2)mC(xe2x95x90Q)OR, xe2x80x94C(xe2x95x90O)N(R)2, xe2x80x94OR, xe2x80x94SO2R, xe2x80x94C(xe2x95x90O)N(H)(NHR), xe2x80x94(CH2)n(OAr), xe2x80x94(CH2)n(OR), xe2x80x94(CH2)mC(xe2x95x90NH)NH2, or xe2x80x94(CH2)nNHRAr;
R2 and R3 are independently H, halogen, xe2x80x94N3, xe2x80x94CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, xe2x80x94(CH2)mN(R)2, xe2x80x94(CH2)mNH(Aa), xe2x80x94(CH2)mNC(xe2x95x90O)R, xe2x80x94(CH2)mC(xe2x95x90O)NHOR, xe2x80x94(CH2)mC(xe2x95x90O)OR, xe2x80x94(CH2)CmC(xe2x95x90O)NH(Aa), xe2x80x94(CH2)mC(xe2x95x90O)N(R)2, and xe2x80x94(CH2)nC(xe2x95x90O)NH(Aa), with the proviso that R2 and R3 cannot both be H;
R4 and R5 are independently H, halogen, xe2x80x94NO2, xe2x80x94CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, substituted or unsubstituted primary amine or secondary amine, xe2x80x94NHC(xe2x95x90O)R, xe2x80x94NHC(xe2x95x90Q)NHC(xe2x95x90O)OR, xe2x80x94NH(Cxe2x95x90Q)NHR, xe2x80x94QR, xe2x80x94OC(xe2x95x90O)N(R2), xe2x80x94C(xe2x95x90O)OR, and xe2x80x94OSi(R)3, with the proviso that R4 and R5 cannot both be H;
Ar is aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl;
Aa is xe2x80x94CX(NH2)CO2H, wherein X signifies a group that completes a natural or synthetic amino acid;
R is H, a substituted or unsubstituted straight chain, branched or cyclic lower alkyl, lower alkenyl or lower alkynyl, or a substituted or unsubstituted Ar or (CH2)nAr;
Q is O or S;
Z is O or S;
a and b are each a single or double bond, and when a is a double bond, only R2 or R3 is present;
m is 0, 1 or 2;
n is 1, 2 or 3;
and pharmaceutically acceptable salts or prodrug forms thereof.
Preferred are compounds of the formula (I) or a pharmaceutically acceptable salt or prodrug form thereof wherein Z is O.
More preferred are compounds of the Formula I, having the formulae II, III, and IV, wherein the substituents are as defined above: 
Still more preferred are compounds of the formula (I) or a pharmaceutically acceptable salt or prodrug form thereof wherein R2 and R3 are independently H, halogen substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, xe2x80x94(CH2)mC (xe2x95x90O)OR, and xe2x80x94(CH2)mC(xe2x95x90O)NH (Aa) with the proviso that R2 and R3 cannot both be H; one of a or b is a double bond; and m is 0.
Most preferred are compounds of the formulae (II-IV) or a pharmaceutically acceptable salt or prodrug form thereof wherein R1 is H; R2 and R3 are independently H, halogen, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, xe2x80x94(CH2)mC(xe2x95x90O)OR, xe2x80x94(CH2)mC(xe2x95x90O)N(R)2 and xe2x80x94(CH2)mC(xe2x95x90O)NH(Aa) with the proviso that R2 and R3 cannot both be H; R4 and R5 are independently H, halogen, xe2x80x94NO2, xe2x80x94CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, substituted or unsubstituted primary amine or secondary amine, and xe2x80x94QR, with the proviso that R4 and R5 cannot both be H; m is 0; Q is O; and Z is O.
Particularly preferred are compounds of the formula (I) or a pharmaceutically acceptable salt or prodrug form thereof wherein R1 is alkyl, alkylfluorophenyl, alkyl nitrile; R2 or R3 is H, halogen, ethyl, propyl, benzyl, fluorobenzyl, xe2x80x94C(xe2x95x90O)OR, xe2x80x94C(xe2x95x90O)OAa and xe2x80x94C(xe2x95x90O)N(R)2 with the proviso that R2 and R3 cannot both be H, R4 and R5 are independently H, halogen, alkoxy, xe2x80x94OR, substituted or unsubstituted piperazinyl with the proviso that R4 and R5 cannot both be H; and a and b are single bonds.
Specifically preferred compounds of the present invention include:
3(R,S)-Carboxyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
1,3-Diethyl-3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-Carboxyl-1,3-diethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
1-Ethyl-8-methoxy-7-[(4-methylpiperazin)-1-yl)]-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-tert-Butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-tert-Butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
7-Bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-tert-Butoxycarbonyl-7-[(4-tert-butoxycarbonylpiperazin)-1-yl]-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-Carboxyl-1-ethyl-8-methoxy-7-(piperazin-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one hydrochloride;
3(R,S)-tert-Butoxycarbonyl-1-ethyl-8-methoxy-2,3-dihydro-1H-1-benzazepine-2-one;
7-Bromo-3(R,S)-carboxyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-tert-Butoxycarbonyl-1-ethyl-8-methoxy-7-(piperazin-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
1,4-Di-[(3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine)-7-yl]-piperazine;
1,4-Di-[(3(R,S)-carboxyl-1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine)-7-yl]-piperazine;
7-[(4-tert-butoxycarbonylpiperazin)-1-yl]-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
1-ethyl-8-methoxy-7-(piperazin-1-yl)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one hydrochloride;
1-tert-Butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-tert-Butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
7-[(4-benzyloxycarbonyl)piperazin-1-yl]-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3,7-dibromo-1-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
7-bromo-1-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
7-bromo-3(R,S)-N-(tert-butyl)aminocarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
7-Bromo-3(R,S)-tert-butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
8-(tert-butyldimethylsilyloxy)-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
3(R,S)-tert-butoxycarbonyl-1-cyanomethyl-8-methoxy-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one;
7-[(4-Benzyloxycarbonyl)piperazin-1-yl]-3(R,S)-tert-butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one; and
7-Bromo-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one or a pharmaceutically acceptable salt or prodrug form thereof.
In the present invention it has been discovered that the compounds above are useful as inhibitors bacterial growth, and for the treatment of bacterial infections.
The present invention also provides methods for the treatment of bacterial, viral or fungal infection by administering to a host infected with bacteria, virus or fungus a pharmaceutically effective amount of a compound of formula (I) 
wherein:
R1 is H, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, xe2x80x94(CH2)mC(xe2x95x90O)R, xe2x80x94(CH2)mC(xe2x95x90Q)OR, xe2x80x94C(xe2x95x90O)N(R)2, xe2x80x94OR, xe2x80x94SO2R, xe2x80x94C(xe2x95x90O)N(H)(NHR), xe2x80x94CH2(OR), xe2x80x94(CH2)n(OAr), xe2x80x94(CH2)mC(xe2x95x90NH)NH2, and xe2x80x94(CH2)nNHAr;
R2 and R3 are independently H, halogen, xe2x80x94N3, xe2x80x94CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted xe2x80x94Ar or xe2x80x94(CH2)nAr, xe2x80x94(CH2)mN(R)2, xe2x80x94(CH2) mNH(Aa), xe2x80x94(CH2)mNC(xe2x95x90O)R, xe2x80x94(CH2)mC(xe2x95x90O)OR, xe2x80x94(CH2)mC(xe2x95x90O)NH(Aa), xe2x80x94(CH2)mC(xe2x95x90O)N(R)2, and xe2x80x94(CH2)nC(xe2x95x90O)NH(Aa);
R4 and R5 are independently H, halogen, xe2x80x94NO2, xe2x80x94CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted Ar or xe2x80x94(CH2)nAr, substituted or unsubstituted primary amine or secondary amine, xe2x80x94NHC(xe2x95x90O)R, xe2x80x94NHC(xe2x95x90Q)NHC(xe2x95x90O)OR, xe2x80x94NHC(xe2x95x90Q)NHR, xe2x80x94QR, xe2x80x94OC(xe2x95x90O)N(R2), xe2x80x94C(xe2x95x90O)OR, and xe2x80x94OSi(R)3;
R is H, a substituted or unsubstituted straight chain, branched or cyclic lower alkyl, lower alkenyl or lower alkynyl, or a substituted or unsubstituted Ar or (CH2)nAr;
Q is O or S;
Z is O or S;
a and b are each a single or double bond, and when a is a double bond, only R2 or R3 is present;
m is 0, 1 or 2;
n is 1, 2 or 3;
and pharmaceutically acceptable salts or prodrug forms thereof.
Alternatively, the present invention provides compounds and methods for the treatment of central nervous system (CNS) disorders, inflammatory diseases, cardiovascular diseases, cancers including angiogenesis, pain, allergic disorders, autoimmune disorders and immunoregulation.
Another aspect of the invention is directed to processes for making the compounds of the present invention, including the steps of introduction of a carboxyl group into the 1-benzazepine skeleton.
The present invention may be more fully understood by reference to the following detailed description of the invention, non-limiting examples of specific embodiments of the invention.
The compounds of the Formula (I) herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.
When any variable (for example, R1 through R5, R, Ar, Aa, Q, Z, m, n, etc.) occurs more than one time in any constituent or in formula (I), or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term xe2x80x9calkylxe2x80x9d means a branched or unbranched saturated aliphatic hydrocarbon radical, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl, and the like. The terms xe2x80x9clower alkylxe2x80x9d and xe2x80x9cC1-C6 alkylxe2x80x9d are synonymous and used interchangeably. A preferred xe2x80x9cC1-C6 alkylxe2x80x9d group is methyl or ethyl.
The term xe2x80x9calkenylxe2x80x9d means a branched or unbranched hydrocarbon radical having the number of carbon atoms designated containing one or more carbon-carbon double bonds, each double bond being independently cis, trans, or a nongeometric isomer.
The term xe2x80x9calkynylxe2x80x9d means a branched or unbranched hydrocarbon radical having the number of carbon atoms designated containing one or more carbon-carbon triple bonds.
The term xe2x80x9csubstituted alkyl, alkenyl, alkynylxe2x80x9d denotes the above alkyl, alkenyl or alkynyl groups that are substituted by one, two or three; halogen (F, Cl, Br, I), nitro, cyano, hydroxy, alkoxy, haloalkoxy, cyclic, branched or unbranched lower alkyl, cyclic, branched or unbranched lower alkenyl, cyclic, branched or unbranched lower alkynyl, protected hydroxy, amino, protected amino, C1-C6 acyloxy, carboxy, protected carboxy, carbamoyl, carbamoyloxy, and methylsulfonylamino. The substituted alkyl, alkenyl, and alkynyl groups may be substituted once, twice or three times with the same or with different substituents.
Examples of the above substituted alkyl groups include but are not limited to: cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(isopropyl), 2-carbamoyloxyethyl and the like. A preferred group of examples within the above xe2x80x9csubstituted alkylxe2x80x9d group includes the substituted methyl group and substituted ethyl group. Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e.g., tetrahydro-pyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, bromomethyl and iodomethyl.
The terms xe2x80x9calkyloxyxe2x80x9d or xe2x80x9calkoxyxe2x80x9d are used interchangeably herein and denote groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
The terms xe2x80x9cacyloxyxe2x80x9d or xe2x80x9calkanoyloxyxe2x80x9d are used interchangeably and denote herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
The terms xe2x80x9calkylcarbonylxe2x80x9d, xe2x80x9calkanoylxe2x80x9d and xe2x80x9cacylxe2x80x9d are used interchangeably herein encompass groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a mono-, bi- or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.
The terms xe2x80x9calkylthioxe2x80x9d and xe2x80x9csubstituted alkylthioxe2x80x9d denote alkyl and substituted alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment of the alkythio or substituted alkylthio group to the group or substituent designated.
The term xe2x80x9cArxe2x80x9d as used herein and in the claims denotes any partially saturated aromatic, or aromatic, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, and heteroaryl generally known to those skilled in organic chemistry and as further described herein below.
The term xe2x80x9cSubstituted Arxe2x80x9d denotes any substituted, partially saturated aromatic, or aromatic, aryl, substituted arylalkyl, and substituted heteroaryl which are generally known to those skilled in organic chemistry and as further described herein below, that include but are not limited to those groups wherein one or more hydrogens are substituted by one, two or three: halogen (F, Cl, Br, I), nitro, cyano, hydroxy, protected hydroxy, alkoxy, haloalkoxy, cyclic, branched or unbranched lower alkyl, cyclic, branched or unbranched lower alkenyl, cyclic, branched or unbranched lower alkynyl, substituted with amino, protected amino, cyano, nitro, aminomethyl, C1-C6 acyloxy, carboxy, protected carboxy, carboxymethyl, hydroxymethyl, carbamoyl, carbamoyloxy, trifluoromethyl, N-(methylsulfonylamino), methylsulfonylamino or other groups specified.
The term xe2x80x9carylxe2x80x9d denotes any mono-, bi- or tricyclic partially saturated aromatic ring or aromatic ring having 5-21 carbon atoms, where at least one ring is a 5-, 6- or 7-membered hydrocarbon ring, and containing from zero to four heteroatoms selected from nitrogen, oxygen and sulfur. Preferred hydrocarbon aryl groups include phenyl, napthyl, biphenyl, phenanthrenyl, naphthacenyl and the like (see Lang""s Handbook of Chemistry (Dean, J. A., ed) 14th Ed., [1992]).
Examples of the term xe2x80x9csubstituted phenylxe2x80x9d include but are not limited to a mono- or di(halo)phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl and the like; a group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-(iso-propoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxyphenyl-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethly)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino)phenyl.
Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl, the 2-aminomethylphenyl and the 3-(N-(methylsulfonylamino))phenyl groups.
The term xe2x80x9carylalkylxe2x80x9d means one, two or three aryl groups having 3 to 14 carbon atoms, appended to an alkyl radical having 1 to 12 carbon atoms including but not limited to: benzyl, napthylmethyl, phenethyl, benzyhydryl (diphenylmethyl), trityl piperazinylmethyl, pyrimidinylethyl, pyridazinylpropyl, indolylbutyl, purinylmethyl and the like.
The term xe2x80x9csubstituted arylalkylxe2x80x9d denotes an alkyl group substituted at any carbon with a C6-C12 aryl group bonded to the alkyl group through any aryl ring position and substituted on the C1-C6 alkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, I), straight chain, branched or cyclic C1-C6 alkyl, straight chain, branched or cyclic C1-C6 alkenyl, straight chain, branched or cyclic C1-C6 alkynyl, hydroxy, protected hydroxy, amino, protected amino, C1-C6 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, C1-C6 alkylthio, N-(methylsulfonylamino) or C1-C6 alkoxy. Optionally, the aryl group may be substituted with one, two or three groups chosen from halogen, straight chain, branched or cyclic C1-C6 alkyl, straight chain, branched or cyclic C1-C6 alkenyl, straight chain, branched or cyclic C1-C6 alkynyl, hydroxy, protected hydroxy, nitro, C1-C6 alkyl, C1-C4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl or an N-(methylsulfonylamino) group. As before, when either the C1-C6 alkyl portion or the aryl portion or both are disubstituted, the substituents can be the same or different.
Examples of the term xe2x80x9csubstituted arylalkylxe2x80x9d include groups such as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl), 5-cyano-3-methoxy-2-phenyl(n-pentyl), 3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hexyl), and the like.
Unless otherwise specified, the terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclic groupxe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d are used interchangeably herein and includes any mono-, bi- or tricyclic saturated, unsaturated or aromatic ring where at least one ring is a 5-, 6- or 7-membered hydrocarbon ring containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, preferably at least one heteroatom is nitrogen (Lang""s Handbook of Chemistry, vide supra).
Preferably, the heterocycle is a 5- or 6-member saturated, unsaturated or aromatic hydrocarbon ring containing 1, 2, or 3 heteroatoms selected from O, N and S. Typically, the 5-membered ring has 0 to 2 double bonds and the 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized, and any nitrogen heteroatom may optionally be quarternized. Included in the definition are any bicyclic groups where any of the above heterocyclic rings are fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred.
The following ring systems are examples of the heterocyclic (whether substituted or unsubstituted) radicals denoted by the term xe2x80x9cheterocyclicxe2x80x9d: thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo-[1,5b]-pyridazinyl and purinyl, as well as benzo-fused derivatives for example benzoxazolyl, benzthiazolyl, benzimidazolyl and indolyl.
Heterocyclic 5-membered ring systems containing a sulfur or oxygen atom and one to three nitrogen atoms are also suitable for use in the instant invention. Examples of such preferred groups included thiazolyl in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. A group of further preferred examples of 5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl; triazolyl, preferably 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl and tetrazolyl, preferably 1H-tetrazol-5-yl. A preferred group of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
Further suitable specific examples of the above heterocylic ring systems are 6-membered ring systems containing one to three nitrogen atoms. Such examples include pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl, preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl radicals are a preferred group. Optionally, preferred 6-membered ring heterocycles are: piperazinyl, piperazin-2-yl, piperidyl, piperid-2-yl, piperid-3-yl, piperid-4-yl, morpholino, morpholin-2-yl and morpholin-3-yl.
The substituents for the optionally substituted heterocyclic ring systems and further examples of the 6- and 7-membered ring systems discussed above can be found in W. Durckheimer, et. al, U.S. Pat. No. 4,278,793.
An optionally preferred group of xe2x80x9cheterocyclicsxe2x80x9d include: 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-oxadiazol-5-yl, 2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl sodium salt, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(N-oxide)-pyridazin-3-yl, 6-hydroxypyridazin-3-yl, 1-methylpyridin-2-yl, 1-methylpyridin-4-yl, 2-hydroxypyrimidin-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]-pyridazin-6-yl.
An alternative group of xe2x80x9cheterocyclicsxe2x80x9d includes: 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1-H-tetrazol-5-yl sodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]pyridazin-6-yl.
The terms xe2x80x9cheteroaryl groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d are used interchangeably herein and includes any mono-, bi- or tricyclic aromatic rings having the number of ring atoms designated where at least one ring is a 5-, 6- or 7-membered hydrocarbon ring containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur, preferably at least one heteroatom is nitrogen. The aryl portion of the term xe2x80x9cheteroarylxe2x80x9d refers to aromaticity, a term known to those skilled in the art and defined in greater detail in xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, J. March, 4th Ed., John Wiley and Sons, New York, N.Y. (1992).
The term xe2x80x9cAaxe2x80x9d as used herein and in the claims refers to xe2x80x9camino carboxylic acidxe2x80x9d as that term is generally understood by those skilled in the art and denotes any group having xe2x80x94CX(NH2CO2H), wherein X signifies a group that completes a natural or synthetic amino acid. Typical natural aminoacids include but are not limited to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenyl-alanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Any other amino acid, natural or synthetic, are contemplated within the scope of this invention.
The term xe2x80x9cprimary aminexe2x80x9d as used herein and in the claims is generally understood by those skilled in the art and denotes any group which is attached to an amine (xe2x80x94NH2) moiety, and includes but is not limited to alkyl-amines, alkenyl-amines, alkynyl-amines, aryl-amines and herteroaryl-amines, as such terms are described herein above.
Examples of primary amines include, but are not limited to any of those listed above, as well as for example, guanidine, methylguanidine, 1,10-diaminodecane, 1,4-diaminobutane, 5-amino-indazole, 7-amino-4-(trifluoromethyl)-coumarin, 4-bromo-3-(trifluoromethyl)aniline, 3-chloro-4-fluoroaniline, 2-chloro-5-(trifluoromethyl)aniline, 3,5-difluorobenzylamine, 2-(difluoromethoxy)aniline, 3-fluoro-p-anisidine, 2-fluoroethylamine, 3-fluoro-4-methylaniline, 4-fluorophenylethylamine, 3-fluoro-d-phenylalanine, 3-fluoro-1-phenylalanine, d,1,-3-fluorophenylalanine, 4-fluoro-3-(trifluoromethyl)benzylamine, 6-fluoro-tryptamine, 5-fluoro-1-tryptophan, 5-fluoro-d,1,-tryptophan, 4-(trifluoromethyl)aniline, 4-(trifluoromethyl)benzylamine, 4-(trifluoromethylthio)aniline, and 2-(4-morpholino)ethylamine.
The term xe2x80x9csecondary aminexe2x80x9d as used herein and in the claims is generally understood by those skilled in the art and denotes any two groups which are attached symmetrically or unsymmetrically to an amino (xe2x80x94NHxe2x80x94) moiety.
Examples of secondary amines include, but are not limited to any of those listed above, as well as for example, piperazine, pyrrolidine, 3-(tert-butoxycarbonylamino)-pyrrolidine, 1-benzylpiperazine, benzyl-1-piperazine carboxylate, 4-benzylpiperidine, 1-(2-chlorophenyl)piperazine, 2,6 dimethylmorpholine, ethyl isonipecotate, ethyl-1-piperazinecarboxylate, 1-(4-fluorophenyl)piperazine, heptamethyleneimine, 1-(2-methoxyphenyl)piperazine, 1-methylhomopiperazine, 1-methylpiperazine, morpholine, 1-(4-nitrophenyl)piperazine, 1-phenylpiperazine, 1-phenylpiperazine, 4xe2x80x2-piperazinoacetophenone, piperidine, 4-piperidinopiperadine, 1-(2-pyridyl)piperazine, 1-(2-pyrimidyl)piperazine, 4-(1-pyrrolidinyl)piperidine, 1,2,3,4-tetrahydroisoquinoline, thiomorpholine, 1-(o-tolyl)piperazine, 1-(xcex1,xcex1, xcex1,trifluoro-m-tolyl)piperazine, 1-(2,3-xylyl)piperazine, tert-butyl-1-piperazinecarboxylate, 1-(2,5-dimethylphenyl)piperazine, 4,4xe2x80x2-bipiperidine, cis-2,6-dimethylpiperazine, and 3,5-dimethylpiperazine.
As used herein, xe2x80x9cpharmaceutically acceptable salts and prodrugsxe2x80x9d refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995, p. 1418, the disclosure of which is hereby incorporated by reference.
Pharmaceutically acceptable acid addition salts are those salts which retain the biological effectiveness and properties of the free bases and which are not biologcially or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
Pharmaceutically acceptable base addition salts are those derived from inorganic bases such as sodium, potasium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug in vivo when such prodrug is administered to a subject. Prodrugs of the compounds of the parent compound are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include, but are not limited to, compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetyl and benzoyl derivatives of amine functional groups in the compounds of the invention and the like.
By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Synthesis
There are many ways well known by those skilled in the art of organic chemistry to prepare the compounds of the present invention. Some of these are described by the General Schemes A to D and specific examples presented below. Each of the references cited below and elsewhere within are hereby incorporated herein by reference in their entireties.
General transformations are well reviewed in xe2x80x9cComprehensive Organic Transformationxe2x80x9d by Richard Larock and the following series: xe2x80x9cOrganic Synthesesxe2x80x9d, Collective Volumes 1 to 9, xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d and xe2x80x9cReagents for Organic Synthesisxe2x80x9d by Fieser and Fieser. Protecting groups may be used when appropriate throughout general and specific schemes of this invention. The choice and use of protecting groups is well known in the art and is not limited to the specific examples bellow. A general reference for protecting group preparation and deprotection is xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d by Theodora Green.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups of the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2xe2x80x2,4,4xe2x80x2-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, 2,2,2-trichloroethyl, xcex2-(trimethylsilyl)ethyl, xcex2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilyl)prop-1-en-3-yl and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the 1-benzazepine molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected 1-benzazepine molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the allyl, tert-butyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents of the 1-benzazepine.
As used herein, the term xe2x80x9camino-protecting groupxe2x80x9d refers to any group typically used in the peptide art for protecting the peptide nitrogens from undesirable side reactions. Such groups include 3,4-dimethoxybenzyl, benzyl, p-nitrobenzyl, di-(p-methoxyphenyl)methyl, triphenymethyl, (p-methoxyphenyl)diphenylmethyl, N-5-dibenzosuberyl, trimethylsilyl, t-butyl dimethylsilyl and the like. Further descriptions of these protecting groups can be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene, 1999, John Wiley and Sons, New York, N.Y.
In general the starting materials were obtained from commercial sources unless otherwise indicated. The compounds of the present invention may be synthesized from the key intermediate 3 shown in General Scheme A. Benzo-fused lactams 3 are conveniently prepared from appropriately substituted xcex1-tetralones which are, in some cases, commercially available. In addition, substituted a-tetralones are well known in the art of organic synthesis and numerous methods for their preparation are published. Conversion of substituted xcex1-tetralones 1 to benzo-fused lactams 3 can be achieved by a number of methods proceeding via the intermediate, corresponding oxime 2, that may be isolated or used as is. Suitable methods for transformation 1 to 3 involve the use of the Beckmann Rearrangement or Schmidt reaction. The key intermediate 3 is then deprotonated with an inert base such as LDA or Li-hexamethyl disilazide and the like. Typically such reactions are carried out in, for instance, but not limited to THF, dioxane, ether at temperatures xe2x88x9278xc2x0 C. to 25xc2x0 C. Numerous electrophilic reagents can capture an anion, formed on xcex1-position relative to amide functionality. In some cases, the intermediate 4 may be again reacted with an inert base in an inert solvent, followed by an attack of an electrophile to give disubstituted products on 3- position of the 1-benzazepine-2-one ring. Subsequently, an alkyl group may be introduced on the hetero-atom as shown in General Scheme A. Typically bases may include, but are not limited to Cs2CO3, K2CO3, NaH, KH while alkylating reagents would include, but are not limited to ethyl bromide, ethyl iodide, diethyl sulfate, 2-bromoethanol and the like. Solvents would include, but are not limited to acetonitrile, acetone, DMA, DMF and the like. Alkylations of this kind are usually run at 25xc2x0 C. to 100xc2x0 C. Thus obtained intermediate 5 may represent a final NCE or may be further elaborated. 
In General Scheme B, the synthetic sequence for an appendage of an amino functionality on aromatic ring of benzo-fused lactams is depicted. Intermediate 5 can be halogenated on the aromatic ring using the methods well known in the art. Preferred halogens are bromo, iodo and chloro because of the feasibility of the subsequent palladium catalyzed coupling reaction. Typically bromination reagents would include, but are not limited to N-bromosuccinimide, N-bromosuccinimide+co-reagent, N-bromoacetamide, bromine, bromine+co-reagent, pyridinium bromide perbromide and the like. Commonly, chloroform, carbon tetrachloride, THF, dioxane, DMF, DMA, DMSO and the like are used as solvents at 25xc2x0 C. to 100xc2x0 C. These reactions require 2 to 12 hours. Intermediate 6 is converted to intermediate 7 by using an analogous methodology to that of palladium catalyzed amination of aryl bromides. Detailed reaction conditions for the latter coupling reactions are summarized in a discussion of the Specific Scheme 3 (vide infra). The method employed is taken from Sadighi J. P., et al. (1998) Tetrahedron Letters 39:5327. Displacement of a halogeno leaving group includes, but is not limited to, nitrogen heterocycles. Other primary and secondary alkyl/aryl amines would also displace Br, Cl and I leaving groups. The 7-bromo of the intermediate 6 is displaced preferentially using a nucleophilic amine such as piperazine, methyl piperazine, tert-butyl 1-piperazinecarboxylate and benzyl 1-perazinecarboxylate. Co-bases such as K2CO3, Cs2CO3, NaOBut, KOBut, K3PO4 and the like are usually used to capture hydrogen halides that are generated in the relevant reactions. This type of reaction is performed in toluene, xylenes, acetonitrile, DMA, THF, DMF at 25xc2x0 C. to 120xc2x0 C. and requires 2 to 48 hours. In Schemes B and C, R4Y represents a compound wherein R4 is defined according to the invention and Y is a leaving group that allows R4 to be inserted into the ring. Y includes but is not limited to xe2x80x94SnBu3 (tributyl tin), Sn(CH3)3 and xe2x80x94B(OH)2. 
In addition to amination of the intermediate 6, carbocyles, aryls and heteroaryls may also be introduced at X on the benzo-fused lactams ring when X is Br, I, Cl or triflate using palladium or cupric catalyzed couplings of tin or boronate carbocycles, aryls and heteroaryls. The relevant methodologies are well known in the art and are described by literature methods such as those published by Chan D. M. T., et al (vide infra); Kamikawa K., et al J. Org. Chem. 1998, 63, 8407-8410 and Stille, et al., Angew. Chem. Int. Ed.Eng.1986, 25,508. Recently reported advances in the field of Suzuki-type reactions include the development of improved conditions for the coupling of arylboronic acids with aryl chlorides catalyzed by either palladium or nickel complexes as reported in the following publications: Tetrahedron Lett. 1997, 38, 5575; Tetrahedron Lett. 1997, 38, 3513; J. Org. Chem., 1997, 62, 8024.
Hydroxy, alkoxy and aryloxy groups may be introduced in 1-benzazepine 2-one system as shown in General Scheme C. It should be noted that groups R1, R2, R3 of the starting compound 8 could be chosen from an array of groups or precursors thereof indicated in the Structural Formula I. When one of the substituents on the aromatic ring of the benzo- fused seven membered lactam is a methoxy group it can be deprotected using BBr3, BI3, AlI3, AlCl3, AlCl3+NaSEt, HBr/AcOH or any other appropriate reagent known in the deprotection art. Solvents such as DCM, chloroform, toluene are generally employed in the latter deprotection reactions which are run at ambient temperature to 70xc2x0 C. and require 2 hours to 48 hours. The resulting hydroxyl group should be protected again in order to further embellish the intermediate 9 according to the synthetic steps that follow those of the General Scheme A. The dimethyl tert-butyl silyl protecting group of the intermediate 12 may be removed by tetrabutylammonium fluoride or acid treatment. 
An alkylation of 13 can be carried out with inert bases such as K2CO3, Cs2CO3, NaHCO3 and the like. Solvents are typically, but are not limited to dioxane, DMF, DMA, and DMSO, acetone, acetonitrile and the like. Temperatures are 25xc2x0 C. to 125xc2x0 C. Alkylating reagents in the latter cases are limited to alkyl and substituted benzyl iodides and bromides.
In a transformation of 13 to 14 where Rxe2x80x3 equals aryl the use of the boronic acids in forming a heteroatom-carbon bond has been employed. Indeed, intermediate 13 appears to be an appropriate substrate for O-arylations with phenylboronic acids and cupric acetate as described by Evans, D. A., et al; in Tetrahedron Lett., 1998, 39, 2937-2940 and Chan D. M. T., et al, in Tetrahedron Lett. 1998, 39, 2933-2936. An alternative methodology for O-arylations is an analogous method to that of the tertiary amine promoted reaction of Nxe2x80x94H bonds with triarylbismuth and cupric acetate. It is known in the art of organic synthesis that phenylboronic acids are also efficient arylating agents and the relevant reaction represents a relatively new, robust, and convenient methodology to arylate Oxe2x80x94H and Nxe2x80x94H bonds containing compounds. Thus, using essentially the same reaction conditions as in the triarylbismuth arylation as originally reported by Burton (Barton, D. H. R., et al; Tetrahedron Lett. 1987, 28, 887-890) one can in many cases replace the bismuth reagent with the corresponding arylboronic acids. We believe that the latter reaction is broadly applicable to a large variety of the substituted 1-benzazepines-2-one substrates and is also very tolerant to many sensitive functional groups. As in the bismuth arylation, the reaction can be performed under very mild reaction conditions, i.e. room temperature and with an amine base. It should be noted that the yield of the reaction can be quite dependent on the nature of the substrate and the substitution on the boronic acid. The choice of the tertiary amine base, i.e., triethylamine versus pyridine also plays a critical role in determining the yield of the reaction. Arylboronic acids in place of triarylbismuth represent an attractive alterantive in O-arylations since a large number of organo boronic acids are either commercially available or their syntheses are well described in the literature. Some arylboronic acids can be obtained from Aldrich Chem Corp. or Lancaster Synthesis Inc., and can be used without further purification.
The phenol type derivative 13 of substituted 1-benzazepine-2-one can be transformed into the corresponding triflate intermediate by any method known in the protecting art. Subsequently, the intermediate 15 can be subjected to a coupling reaction with a variety of the amines using Pd(0) catalyst mediated reactions. When the leaving group is a triflate, organotin reagents and organoboronates may be used with palladium catalysts to render a carbon nucleophile. In this way all sorts of alkyl, aryl and heteroaryl groups may be introduced in the 1-benzazepine-2-one ring as it was discussed before and indicated in the General Scheme B.
In General Scheme D, synthetic methodologies to prepare 1-benzazepines-2-ones bearing an additional oxo group on 5-position and a double bond at different positions of seven membered lactam ring are shown. 
Substituted anilines, exemplified by 17, serve as a starting material, which can be alkylated by using reductive condensation with a variety of aldehydes (alkyl, aryl and heteroaryl). It should be noted that the substituents R3, R4, R5 of the starting aniline 17 can be chosen from an array of groups that are indicated on the aromatic ring in the Structural Formula I. Reductive aminations are well known in the art and are typically performed in alcohols, water/alcohol mixtures or in water/DMF mixtures at temperatures 25xc2x0 C. to 80xc2x0 C. Thus obtained N-alkylated anilines can be further acylated using any 3-chloro 3-oxopropionate (alkyl/benzyl malonyl chloride) as a reagent of choice to synthesize the intermediate 19 as shown in General Scheme D. The ester group of the intermediate 19 can be later in the synthesis transformed into carboxyl, amino carbonyl or hydroxymethyl group. The 19-type intermediates are very well known in the chemistry of quinolones. Elongation of a carbon chain on the hetero-atom with tert-butylbromoacetate, for instance, provides an appropriate substrate for a subsequent Friedel Crafts reaction. Typically these reactions are run in the presence of inert bases such as LDA, Li-hexamethyl disilazide and the like. Solvents would typically include THF, ether, 1,4-dioxane and DMF at temperatures xe2x88x9278xc2x0 C. and 25xc2x0 C.
A cyclization of 20 can be achieved by a number of methods well known in the literature as Friedel-Crafts reaction. A cyclization of 20 to 21 can be effected, for instance, in one pot reaction via the mixed anhydride formed with triflic acid. Introduction of a double bond is examplified but not limited to a conversion of 21 to 22.
Dehydrogenation of the intermediate 21 can be carried out using diphenyl diselenide+LDA, phenylselenyl chloride, DDQ, benzeneselenic anhydride, formed in situ, selenium dioxide in water or any appropriate reagent known in the dehydrogenation art. Typically solvents would include dioxane, THF, benzene, chlorobenzene, acetic acid, ethanol at temperatures 25xc2x0 C. to 120xc2x0 C. These latter reactions usually require 2 hrs to 48 hours.
When a prolongation of the chain on the hetero-atom of the intermediate 19 is effected by using bromoacetaldehyde ethylene acetal, for instance, in the presence of inert bases such as LDA or Cs2CO3 the intermediate 23 is obtained.
Subsequent cyclizatin of 23, followed by a dehydration in strong acidic reaction conditions affords the desired compound 24. Typically strong acids would include p-toluene sulfonic acid or PPA at elevated temperatures. 24 can be considered a NCE or an intermediate that can be further embellished.
Specific compounds depicted by a general formula I of the present invention can be prepared from 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) as a common intermediate. The preparation of some key intermediates and final NCEs are described in the following reaction schemes:
Schemes 1, 2, 3, 4, 5, and 6. The syntheses of some intermediates in this instant invention are described in a narrative way.
8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) is conveniently prepared from 7-methoxy-1-tetralone (1A), using known procedures described by Eaton, et al, J. Org. Chem. (1973) 38, 4071. 7-Methoxy-1-tetralone, which is commercially available, was transformed to 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) via the corresponding oxime (2A) followed by the Beckmann rearrangement as illustrated in Scheme 1. The Beckmann rearrangement can be achieved by a number of methods well known in the literature, including treatment of 7-methoxy-1-tetralone oxime (2A) with methanesulfonic acid and anhydrous phosphorous pentoxide at elevated temperatures. 
8-Hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was designed to investigate utility of boron tribromide as a deprotective agent for the 1-benzazepine-2-one substrate bearing methoxy group. Deprotection of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one using BBr3 in DCM was successful. Other substituted 1-benzazepine-2-ones bearing the methoxy functionality are deemed to be subjected to the above-mentioned deprotection. Therein also lies a problem-applicability of this deprotection reaction conditions to 8-methoxy-1-benzazepine-2-ones bearing tert-butoxycarbonyl group.
Conversion of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) to the 3-ethoxycarbonyl intermediate (4A) can be achieved by a number of methods familiar to those skilled in the art. A suitable method involves use of LDA and diethyl carbonate or diethyl pyrocarbonate. It was observed that carboxylation easily occurred on unprotected 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) while the same reaction failed when 1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was employed as a starting material. 3(R,S)-Ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4A) was protected on the hetero-atom using iodoethane as an alkylating agent in a cesium carbonate mediated reaction. A saponification of 1-ethyl-3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5A) in basic reaction conditions afforded the desired NCE, 3(R,S)-carboxyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (6A).
When 3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4A) was treated with two equivalents of sodium hydride as a base and iodoethane as an alkylating reagent dialkylation was observed resulting in a formation of 1,3-diethyl-3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (7A) as illustrated in Scheme 2. Further saponification in basic reaction conditions produced 1,3-diethyl-3(R,S)-carboxyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (8A). 
As shown in Scheme 3, 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) was alkylated using iodoethane as an alkylating reagent and one equivalent of sodium hydride as a base to provide 1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (9A). A bromination in methanol at ambient temperature using bromine as a brominating agent afforded exclusively 7- bromo regioisomer (10A) which was transformed further employing a catalytic cross coupling methodology. This coupling reaction was conveniently carried out by use of 4-methylpiperazine as a reagent, BINAP as a chelating reagent, palladium acetate as a catalyst in the presence of cesium carbonate as a base. 
Syntheses of 3(R,S)-carboxyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (6A) and 3(R,S)-carboxyl-1-ethyl-8-methoxy-7-piperazinyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (6B) have been designed in such a manner that a common route proceeds via the intermediacy of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A). In this particular reaction sequence as illustrated in Scheme 4, 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) was transformed to the 3(R,S)-ethoxycarbonyl (2B) and 3-tert-butoxycarbonyl (1B) derivatives of their common precursor using diethyl pyrocarbonate or di-tert-butyl carbonate, respectively. 3(R,S)-tert Butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (1B) was chosen as a preferable intermediate over its ethyl ester counterpart due to a higher yield in the relevant carboxylation step. Furthermore, it is a common knowledge that tert-butyl ester groups are easier to be removed than ethyl ester groups. A protection of the heteroatom was effected by using iodoethane as an alkylating reagent in a cesium carbonate mediated reaction. 
1-tert-Butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was obtained in a low yield as a side product in a synthesis of 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one. To improve the yield in a synthesis of 1-tert-butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one, 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was exposed to di-tert-butyl dicarbonate in a cesium carbonate or sodium hydride mediated reaction. Indeed, the desired 1-tert-butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was obtained in good yield.
A synthesis of 3-tert-butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one demonstrated that substituted 1-benzazepine-2-ones are appropriate substrates for benzylic alkylation on the hetero-atom.
A bromination of 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3B) using N-bromosuccinimide as a brominating reagent in the presence of a catalytic amount of acetic acid produced exclusively 7-bromo regioisomer (4B). The same bromination procedure was used to synthesize the 7-bromo derivatives of 3(R,S)-tert-butoxy carbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one and 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one. A formation of 7-bromo-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one indicated that a bromination of 1-benzazepine-2-one skeleton could be performed although the heteroatom is unprotected. Bromination of 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one with NBS and a catalytic amount of benzoyl peroxide (BPO) in carbon tetrachloride resulted in 7-bromo-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one.
Conversion of 7-bromo-3(R,S)-tert-butoxy-carbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4B) to the requisite 7-piperazinyl derivative can be achieved by a number of cross coupling methodologies familiar to those skilled in the art including that described by L. Buchwald, et al, Tet. Lett. (1998) 39, 5327-5330. The chelating ligand BINAP in combination with palladium acetate forms a highly effective catalyst system for the coupling of anilines with aryl bromides. This catalyst system is effective in coupling reactions involving a variety of substrates, including electron poor anilines or electron-rich aryl bromides. In addition, this cross coupling reaction tolerates a high degree of steric congestion at both aniline and aryl bromide. We have employed the latter cross coupling methodology for the coupling of piperazine/protected piperazine with an electron rich arylbromide moiety, which probably exhibits steric congestion at the reactive site imposed by a bulky ortho methoxy group. Precisely, a cross coupling of 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4B) with 1-tert-butoxycarbonyl-piperazine in the presence of BINAP as a chelating reagent, palladium acetate as a catalyst and sodium tert-butoxide as a base gave 3(R,S)-tert-butoxycarbonyl-7-[(4-tert-butoxycarbonyl-piperazine)-1-yl]-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (5B) as a penultimate precursor of the desired NCE. Deprotection of piperazine moiety of the molecule and removal of tert-butyl ester group in a one pot reaction using a concentrated solution of hydrochloric acid in dioxane provided 3(R,S)-carboxyl-1-ethyl-8-methoxy-7-piperazinyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one hydrochloride salt (6B). Furthermore, utilization of 1-benzyloxycarbonylpiperazine as a secondary amine component in the former cross coupling reaction offered 7-[(4-benzyloxycarbonyl)piperazin-1-yl]-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one when 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was used as a starting compound. Thus, a strategy of cross coupling of a piperazine/protected piperazine with an electron rich heteroarylbromide has considerable flexibility to vary structure and should be a versitile route to the preparation of biologically active anti-infectives using automatic parallel syntheses. A synthesis of 1-ethyl-8-methoxy-7-piperazinyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one hydrochloride was executed via 7-[(4-tert-butoxycarbonylpiperazin)-1-yl]-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one as an immediate precursor.
7-[(4-Benzyloxycarbonyl)piperazin-1-yl]-3-tert-butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one has been thus far the most complex ring system in our development of new strategies for syntheses of the 1-benzazepine anti-infectives.
When 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3B) was treated with N-bromosuccunimide in the presence of a catalytic amount of benzoyl peroxide at elevated temperature, a bromination probably occurred at the benzylic position as illustrated in Scheme 5. A consequent elimination of HBr afforded 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3-dihydro-1H-1-benzazepine-2-one (7B). 
Several derivatives of 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4B) were prepared as depicted on Scheme 6. Removal of an ester group using concentated trifluoroacetic acid at ambient temperature afforded 7-bromo-3(R,S)-carboxyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (8B). A cross coupling reaction of 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4B) with piperazine in the presence of BINAP as a chelating reagent, palladium acetate as a catalyst and cesium carbonate as a base gave 3(R,S)-tert-butoxy carbonyl-1-ethyl-8-methoxy-7-piperazinyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (9B). A low yield in this cross coupling reaction was due to a formation of 1,4-di-[(3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine)-7-yl]-piperazine (10B). Saponification of 1,4-di-[(3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine)-7-yl]-piperazine using concentrated trifluoroacetic acid as a deprotecting reagent produced 1,4-di-[(3(R,S)-carboxyl-1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine)-7-yl]-piperazine (11B). 
When 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was treated with bromine in MeOH at ambient temperature, bromination occurred at 3-position of the 1-benzazepine-2-one ring system. In addition, a transesterification due to the presence of methanol was observed which resulted in a formation of 7-bromo-3(R,S)-methoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one.
Replacement of an ester functional group by an aminocarbonyl group in the substituted 1-benzazepine-2-one system has been succesfully employed in a synthesis of 7-bromo-3(R,S)-N-(tert-butyl)aminocarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one. The latter compound was synthesized by a coupling reaction of 7-bromo-3(R,S)-carboxyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one with tert-butyl amine using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT) and triethylamine as reaction mediators. A series of N-terminal groups of the aminocarbonyl functionality are under investigation. This amide bond formation offers a possibility of the use of an appropriately protected amino acid as an amino component. In addition, it is perceived that this coupling strategy could be used to introduce a peptidomimetic side chain on 3-position of the 1-1-benzazepine-2-one ring system including hydrophobic spacers, such as substituted 4-aminobenzoyl group.